Morpholine periodide



v Patented. July MORPHOLINE mmromm': Robb v. Rice, Hasbrouck Heights, 1v. 1., and

George D.

Beal, Pittsburgh, Pa.,

assignors to Gane and Ingram, Inc., New York, N. Y., a corporation of New York No Drawing. Application Serial No. 324,0

March 15, 1940, as g This invention pertains to iodine compounds for medicinal and other applications, and its principal object is .to provide such a compound which is capable of slowly liberating free iodine in the presence of moisture for treating fungus and like growths as well as bacterial infectionsof body tissues without injuring the tissues.

Considerable dimculty has been experienced in developing an inexpensive and harmless yet efiective treatment for certain body fungus infections, such for example as that commonly termed athletes foot. Although iodine has long been recognized as one of the most effective fungicidal medicines known, its use as such has heretofore met with little success, since materials previously developed for this treatment are either incapable of liberating free iodine under conditions encountered in external body applications, or alternatively, provide this element in such high concentration initially or by too rapid liberation thereof, as to injure the skin and body tissues by corrosive action.

For example, iodine solutions, such as tincture of iodine, if of sufiicient strength to be eifective, provide too high concentration of free iodine, and hence injure the tissues. The same is true of inorganic iodine compounds which are capable of producing free iodine under the conditions encountered for external body application, inasmuch as such inorganic compounds liberate iodine almost instantaneously in the presence of moisture. On the otherhand, the known types of organic iodine compounds which have been shown to possess some bactericidal activity, such for example as iodoform, tetraiodopyrrole, diiodopiperazine, iodine derivatives of hexamethylenetetramine, etc., are all limited to use as a source of iodine for internal administration, because none will liberate iodine when applied externally. Any bactericidalactivity present under these conditions is a result of the properties of the compound as a whole and is not due to liberation of free iodine. None of the organic compounds aforesaid is particularly effective as a fungicidal agent.

The problem of preparing a suitable fungicidal agent is, therefore, one of providing a material capable of gradually liberating free iodine under the conditions of moisture, etc., en-

countered in external body application, and at r such a rate as to produce an iodine concentration insuiiicient to cause harmful corrosive action on the body tissues but suflicient to efiect pronounced fungicidal or bactericidal activity. Organic iodine compounds in which the iodine isbound to-a carbon atom are not jsuitable, since such chemicals are either too stable to liberate iodine under the'conditions stated, or do so only in the form of hydriodic acid in which the iodine'is combined with a hydrogen atom, and hence results in chemical activity of entirely different characteristics from those of free iodine. And although it is known that iodine will combine with the nitrogen atom of certain nitrogen compounds, particularly the nitrogen of an amino group, to form rather easily decomposable iodine compounds, such compounds of this type as have heretofore been known are nevertheless either too stable to liberate free iodine under the'conditions encountered in external body application or for other reasons are not suitable to be used in therapeutic preparations. In most of the known compounds of this type, the iodine substitutes for hydrogen on the nitrogen atom so that a further substitution of some other element for iodine is required to liberate the latter. That is to say, free iodine will not be liberated on mere exposure to external body conditions. We have discovered, however, in accordance with the basic concept of the present invention, that in the case of morpholine, iodine may be combined with the nitrogen atom by direct addition thereto, rather than by substitution for hydrogen, and that the iodine thus combined will be slowly liberated again as free iodine, in aqueous solution or in the presence of moisture, such as is encountered in externalbody application. This iodine-morpholine addition product is, therefore, ideally adaptedto thetreatment of fungus growths and the like, inasmuch as the iodine is liberated at a sufficiently slow rate to kill the fungus growth without injuring the body tissues.

More particularly in accordance with the invention, we have discovered that if morpholine is allowed to react with iodine in a suitable solvent, as for example an aqueoussolution of potassium iodide, that an orange-red, crystallineprecipitate is formed which, on separation and analysis, is found to have the formula:

. mt H30 CHz {PIX and which, accordingly, followingthe accepted nomenclature, is morpholine periodide. This compound results from the following addition reaction of morpholine and iodine:

It will be observed that in accordance with this reaction, two atoms of iodine combine by addition with each molecule of morpholine to i'ormthe resulting addition product, morpholine periodide. In so far as I am aware, it has not heretofore been known that iodine would combine with morpholine, or that an addition product, such as morpholine periodide, would result. This compound, therefore appears to be new.

The new compound, morpholine periodide, has,

as would be expected, properties quite diilerent from those of the compounds referred to above in which an iodine atom substitutes for hydrogen on a nitrogen atom. For example, in the presence of water or moisture, the new compound, viz., the periodide, gradually decomposes with the liberation of free iodine. This is evident from the characteristic iodine odor produced. When starch-iodide paper is immersed in water containing the new compound, the paper immediately turnsblue, thereby establishing the presence of free iodine in the water, the latter being liberated from the morpholine periodide.

Although the morpholine periodide gradually decomposes in the presence oi water or moisture,

it is suificiently stable to be prepared in the manner above described. The precipitate formed, however, should be dried as rapidly as possible to prevent the liberation of iodine and, when dried, it is perfectly stable so long as it is kept in a closed container.

For treating fungus growths and the like, the new compound may be applied to the skin as such or incorporated in a suitable ointment base, dusting powder, solution or other form of pharmaceutical preparation without causing irritation and corrosive action characteristic of free iodine. The natural secretion of perspiration. through the skin produces suflicient moisture to liberate free iodine from the morpholine. perio-- dide when it is placed on the body; and the iodine is liberated in sufllcient concentration to kill bacteria and fungi without harming the body tissues. Within certain limitations, the new compound can be incorporated into any preparation that is used to produce a germicidal or fungicidal action. These limitations consist in preparations which in'g morpholine periodide from morpholine and iodine. Elementary iodine may be added to morpholine in the absence of any solvent, whereupon a reaction occurs to produce morpholine periodide. However, this mode of preparation is subject to the objection that the morpholine periodide formed in the reaction produces a coatin: on the particles of iodine immersed in themorpholine, and thus noticeably hinders the reaction from proceeding to completion.

The compound is best prepared by using some solvent to dissolve the iodine and the morpholine, among which may be mentioned methyl or ethyl alcohol, acetone and water. If water is used, potassium iodide must be dissolved in the portion reserved for making the solution of iodine to be added to the solution of morpholine or vice versa. The above solvents are mentioned by way of example only and other suitable solutions may be employed.

Water containing potassium iodide as the iodine soiubilizing agent, is a very elfective solvent inconducting the reaction, since the morpholine periodide formed does not react with contain water, alcohol, aceton and similar substances that will react with the compound. Morpholine periodide may also be used for internal administration where a systemic iodine'efthe water to form any secondary and undesirable compounds, such as is the case when certain other solvents are used. For example, when ethyl alcohol or a mixture of ethyl alcohol and water is used, appreciable quantities of iodoform are produced by secondary reactions, and the iodoform thus produced contaminates the morpholine periodide to such an extent that its removal is difllcult.

On the other hand, when iodine is dissolved in an aqueous solution of potassium iodide, and this solution is added to the morpholine dissolved in water, orange-red, crystalline morpholine periodide soon begins to separate from the solution and continues to do so until one or both of the reactants has been entirely consumed. The same action occurs if the order of addition is reversed and the morpholine solution is added to the iodine solution. The precipitate formed may be filtered oil. on a Buchner funnel, washed thoroughly with water, and dried at room temperature or slightly above, preferably under vacuum, since exposure to air while moist causes morpholine periodide to darken due to liberation of iodine. When the material is thoroughly dried, it may, as stated, be stored in glass containers indefinitely without appreciable decomposition.

As a specific example of the new compound, we give the following:

A solution of iodine is prepared by dissolving 965 grams of iodine in a solution composed of 1800 cc. of water and 1800 grams of potassium iodide. This solution is then added dropwise to 340 grams of morpholine dissolved in 3000 cc. of

- water during constant stirring. Soon after the feet is desired. The compound can be administered as such or in combination with othenmaterials which do not react before effected.

The new compound morpholine periodide may medication is also be used for purposes other than medicinal.

addition of iodine is begun, fine, orange-red crystals of morpholine periodide start to separate and more of the compound continually crystallizes out as more iodine is added. When all the iodine has been introduced, stirring is stopped and the precipitate of morpholine periodide is filtered off, washed with 1500 cc of water and pressed as dry as possible. Th filter cake is then removed and dried in a vacuum desiccator over calcium chloride at a pressure of about 50 mm. for three days. The yield is 1250-1275 grams of morpholine periodide, or 96-98 per cent. 01 the calculated amount. Iodine analysis: 74.71 per cent.;ca1culated-74.38 per cent.

For external application, the new compound may be employed as such in powder form, or in aqueous, alcoholic, etc., solution, or incorporated in a dusting powder or in a suitable ointment base, etc. When used in a dusting powder for example, it may be combined with powdered talc in the ratio of about 90 parts by weight of powdered tale to 10 parts by weight of the crystalline morpholine periodide, although these proportions are not critical. In general, the proportions are to be determined by the strength of the medicinal action required.

An excellent salve containing the morpholine periodide is obtained by incorporating 10 parts by weight of this ingredient in 90 parts by weight of a polyglycol wax of the proper consistency, for example, "Carbowax 1500, a product of Carbide and Carbon Chemicals Corporation. Such an ointment base is especially adapted for fungus growth treatments in conjunction with the morpholine periodide, because it is water-soluble and also because it facilitates the liberation of free iodine from the morpholine periodide in the presence of moisture. Another desirable feature is that the morpholine periodide goes into solution in this ointment base, in contrast to its substantial insolubility in other common ointment bases, such as petrolatum, lard, lanolin, etc. The consistency of the ointment base can of course be varied by controlling the extent to which polymerization is carried. Also if any given batch is too firm or viscous, it can be conveniently thinned down to the desired consistency by the addition of such agents as glycerine, Cellosolve, etc., the former being preferred. The quantity of the thinning agent added will of course depend upon the consistency of the original ointment base and the consistency of the product desired. The consistency as manufactured is usually varied somewhat throughout the year in accordance with seasonal variations in temperature.

We claim:

1. A therapeutic agent for releasing elemental iodine comprising, morpholine periodide in a nonaqueous and non-reacting dispersing medium.

2. A therapeutic agent for releasing elemental iodine comprising, morpholine periodide in a non-aqueous and non-reacting liquid dispersing medium.

3. A therapeutic agent for releasing elemental iodine comprising, morpholine periodide in a nonaqueous and non-reacting ointment base.

4. A therapeutic agent for releasing elemental iodine comprising, an anhydrous powder comprising morpholine periodide and a non-reacting dispersing agent.

ROBB V. RICE. GEORGE D. BEAL. 

